Organ-on-a-chip systems: limited validity?

Organ-on-a-chip systems are technically a great enhancement of medical research because they facilitate testing of active ingredients on cell cultures in the chambers of a plastic chip. This replaces animal testing and improves patient safety. That being said, they are not a true-to-life replication of the human body and can only simulate a few functions and activities. This begs the question of whether their results are actually applicable.

In this interview with MEDICA-tradefair.com, Prof. Thomas Korff talks about the possibilities and limitations of organ-on-a-chip technologies, explains their advantages in laboratory analytics and describes the role they might play in medical research in the future.

Prof. Korff, what are the limitations of organ-on-a-chip technologies?

Prof. Thomas Korff: During my doctoral thesis on organoids back in the late nineties, I had seen firsthand how much people are interested in this technology, what researchers can achieve with it, and how quickly they can get answers to questions when these systems work as intended. However, this immediately also reveals the limitations of this technology: organ-on-a-chip systems are reductionist models of a living organism, i.e., specifically matched organ systems in which the individual components of the organism interact with each another. The system illustrates organs and their functions quite well and answers questions pertaining to simple disease models, such as lung infections, or the cell-specific effects of therapeutic agents. This process is more difficult when it comes to complex, multifactorial or chronic diseases like atherosclerosis. What’s more, the chips can so far not be used as it pertains to the nervous system, making it impossible to study any pain management or medication options. Complexity is our limitation in this setting: we are unable to represent the body as such, but only various organ-specific functions.

What are the best applications for these systems?

Korff: Thanks to the specific structure, the systems are essential in answering accurately defined questions. For example, you can use liver and kidney cells to conduct toxicity and metabolic testing and determine how fast drugs are broken down, what concentrations cause cell injury and how the ingredients are being metabolized. In some instances, organ chips are already being used to test for responses to therapeutic antibodies, with the goal to use them in humans at a later point.

One ulterior motive here is to prevent animal testing of course. Where is this type of testing still unavoidable?

Korff: Needless to say, it is ethically desirable to reduce the suffering of laboratory animals or to stop using them entirely if possible. However, human beings are also capable of pain and suffering, which is why we must ask ourselves whether it would be ethical to use a drug on humans before it has been tested on another sentient being. Organ-on-a-chip models are unable to assist in this endeavor because they lack complex neuron structures and mental capacity. I am certain that as long as the models are unable to reproduce systemic responses – meaning responses affecting the whole body -, animal testing remains unavoidable because certain effects cannot be captured using reductionist systems. Oftentimes legislature also mandates testing on animals before drugs are considered for human use.

Are these test results actually applicable due to the reductionist approach of organ-on-a-chip systems?

Korff: They are absolutely applicable for specific, defined issues. However, the danger here is to generalize things. For example, when I test a substance in an organ-on-a-chip system that combines lung, liver, kidney and intestinal cells, and I do not detect any adverse effects, I can only conclude that it has no harmful effects in this particular system and these cells. A false conclusion would be to infer that there would be no side effects on other types of cells. It means that I am able to answer a predefined specific research question pertaining to the test system. However, I am unable to make any or only limited statements about what happens at a systemic level or in another functional context.

Where do you ultimately see the benefits of an organ-on-a-chip system?

Korff: One advantage is that it allows us to use human cells. Many findings from animal testing are not applicable to humans at a ratio of 1:1 because human cells simply react differently and can sometimes exhibit higher or lesser tolerance to drugs. Whether there is an increased level of transferability of organ-chip results still remains to be seen. We first need a fundamental standardization of test systems, which are still very heterogeneous, depending on the country and laboratory.

What’s more, the chips enable different specific and standardized tests, which can be broken down fairly quickly to a cell-specific analysis. Meaning you can create a very specific profile of cell-specific responses if the system is set up accordingly. This is very difficult to do inside the body because it always involves many different types of cells that respond at the same time. However, analysis becomes increasingly more difficult with more complex systems.

What role could these systems play in medical research of the future?

Korff: If they are truly becoming more sophisticated, I could envision predictive models to project drug side effects at the cellular level, which would be impossible to do using animal models. For example, you could fairly quickly determine which active ingredients should be pursued as contenders in clinical trials.

Which problems still need to be solved before chip systems can be used more frequently?

Korff: We clearly need standardization to be able to compare and interpret findings. This is a process that already starts with the cells that are being used. Some research groups use primary cell cultures and other cell lines, while others try to differentiate stem cells into specialized cells for specific organs. Other issues include the formulation of cell culture media, the cell life cycle on the chips or the materials used in bioprinting for example. These are all variables that could impact results. That's why organ chips still have a long way to go before they can replicate the complexity of living organisms.